1. Field of the Invention
This invention relates to the relationship between infection with adipogenic adenoviruses, such as, for example, adenovirus-36 (Ad-36), and the etiologies of obesity and obesity-related cancers and other diseases. More specifically, the invention relates to methodology for predicting whether a subject is predisposed to developing breast cancer or prostate cancer. Additionally, the invention relates to assaying a subject for Ad-36 status and using Ad-36 status as a marker for the presence of cancer, to predict the future risk of developing such cancer, and/or to predict the aggressiveness and prognosis of cancer.
2. Related Art
There has been a dramatic simultaneous increase in the prevalence of obesity and of certain types of cancer. A worldwide epidemic of obesity accelerated dramatically starting about 1980. In the USA the prevalence of obesity in adults more than doubled in the 20 years from 1980 to 2000 (from 15% to 31%), whereas the prevalence increased only slightly in the prior 20 years from 1960 to 1980 (from 13.5% to 15%). The prevalence of obesity in children tripled from about 1970 to 2000. Likewise, cancers of the breast, prostate, colon, and liver have also rapidly increased in prevalence in recent years.
Changes in reproductive hormones in obesity have been suggested to play a role in the association of breast and prostate cancer (among others) and in the aggressiveness of these cancers. However, changes in reproductive hormones cannot explain cancers such as colon, renal, or pancreatic cancer that are not under hormonal control.
Another possibility for the link between obesity and cancer is the decreased immune function seen in obese individuals. Obese people have a lower antibody response to vaccination with hepatitis B than vaccine people who are not obese. The immune system is critical in inhibiting the growth of neoplasms, so it would not be surprising if this were the mechanism of increased cancers of many types in obesity. However, adenoviruses are well known to decrease immune function as a way to enhance their replication within the host, including human hosts. More relevant, the SMAM-1 avian adenovirus, which has been reported to cause obesity, had a major impact by decreasing immune function of chickens. Thus, there is a direct link between an adenovirus that causes obesity and that also impairs immune function. The inventor has reported that SMAM-1 is associated with obesity in humans, adding a link from adenovirus to human obesity.
Some human adenovirus serotypes are known to be oncogenic, and induce tumors in rats or hamsters. Adenovirus serotypes are divided by Groups. Group A adenoviruses (e.g., Ad-12, Ad-18) are highly oncogenic, producing tumors in most animals within 4 months; group B adenoviruses (e.g., Ad-3, Ad-7) are weakly oncogenic, inducing tumors in most animals within 4 to 18 months; group D viruses are thought to be less oncogenic, but serotype-9 efficiently induces mammary tumors within 3 to 5 months. There has been extensive work on adenovirus-induced cancer, but to date, there has been no evidence that adenoviruses cause human cancer.
If adenoviruses cause human cancers, it is likely that they do so by altering expression of genes in the host that allow unregulated cell growth to occur. Many such tumor markers have been identified. Some are due to genetic variants. Hereditary breast cancer has been linked to germline mutations in one allele of high penetrance susceptibility genes such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN. It is possible that adenovirus infections facilitate cancer in these genetically susceptible individuals. However, adenoviruses may contribute to spontaneous oncogenesis by inducing expression of various oncogenes or suppressing expression of tumor suppressor genes of the host. Among the alterations due to adenoviruses that are thought to contribute to cancer are changes in DNA-dependent protein kinase, fatty acid binding protein, mTOR, p16, p53, PDZ protein, phosphatidylinositol 3-kinase, PML, thymidine kinase, and Zip kinase. Of particular interest are those tumor related factors that are altered by the adenovirus E4 region, and specifically the E4orf1 gene. The E4 oncogenes include DNA-dependent protein kinase, p53, PDZ protein, phosphatidylinositol 3-kinase, PML, thymidine kinase, and Zip kinase. As will be described below, the Ad-36 E4orf1 gene has been shown to be involved in producing obesity by a direct effect on adipocyte metabolism. The E4orf1 region of human adenovirus-5 has been shown to be an oncogene, and a recent paper reported that Ad-5 produces obesity in mice. These findings show a direct link between obesity and cancer, with both being due to a human adenovirus, and provide the likely mechanism via a viral gene.
The general consensus of many investigators in the field of cancer research has been that adenoviruses do not contribute to the etiology of human cancer. Therefore, it would be a major technological advance to demonstrate that adipogenic adenoviruses, such as Ad-36, are associated with obesity-related cancers, such as breast and prostate cancers.